1. PULMONARY PATHOLOGY V Acute Lung Injury
Nils Lambrecht, MD, PhD
November 16th, 2015

2. READING ASSIGNMENT Robbins Basic Pathology 9th Edition
Pp – ARDS
PP – Neonatal RDS
Pathoma 2015 Edition:

3. Pulmonary 5 – Acute Lung Injury INTEGRATION REPORT
ANATOMY: Lungs (Wiki) 10/16/14
HISTO: Respiratory Podcast 1/12/15
PHYSIO: Blood Gases (Longmuir) 1/23/15
PHYSIO: Lung mechanics- surfactant (Longmuir) 1/16/15

4. Objectives 1. Learn pulmonary anatomy and histology
2. Define atelectasis
a. Resorption (obstructive) atelectasis
b. Compression atelectasis
c. Contraction atelectasis
3. Define pulmonary edema
a. Hemodynamic pulmonary edema
b. Edema caused by microvascular injury
4. Define acute (non-vascular and non-infectious) lung injury
a. Acute respiratory distress syndrome (ARDS) and diffuse alveolar damage (DAD)
b. Respiratory distress syndrome (RDS) of newborn
c. Acute Interstitial Pneumonitis (Hamman–Rich syndrome)
d. Diffuse alveolar hemorrhage syndromes - Goodpasture syndrome
- Idiopathic pulmonary hemosiderosis
- Pulmonary angiitis (Wegners granulomatosis)

5. The 10 leading causes of death
Significance
The 10 leading causes of death

6. Lung Anatomy (I)

7. Lung Anatomy (II)

8. Lung Histology (I)

9. Lung Histology (II)

10. Atelectasis
Incomplete expansion (neonatal atelectasis) or collapse of previously inflated lung, which is reversible.

11. Occurs when an obstruction prevents air from reaching distal airways:
Mucus
Aspiration
Tumor
Enlarged peribronchial lymph nodes
Associated with accumulation of fluid, blood, or air within the pleural cavity, which mechanically collapses
the adjacent lung.
Local or generalized fibrotic changes in the lung or pleura hamper expansion

12. Poll Everywhere: Question 1
Which of the following is true regarding compression atelectasis?
The mediastinum shifts toward the affected lung.
A pneumothorax may cause this type of atelectasis
A mucus plug in the bronchus may cause this type of atelectasis
The typical histologic picture is edema fluid filling the alveolar spaces
Diffuse fibrosis of lung parenchyma is the most common cause of this type of atelectasis

14. Fluid accumulation in the air spaces of the lungs
Pulmonary edema
Fluid accumulation in the air spaces of the lungs

15. Intra-alveolar hemorrhage
Red blood cell accumulation in the air spaces of the lungs

16. Pulmonary edema/hemorrhage

17. Pulmonary edema 4A

18. Intra-alveolar hemorrhage

19. Hemosiderin-laden macrophages (heart failure cells)

20. Pulmonary edema
HEMODYNAMIC EDEMA
EDEMA DUE TO MICROVASCULAR INJURY

21. Hemodynamic edema Increased pulmonary venous pressure (common)
Left-sided heart failure
Volume overload
Pulmonary venous obstruction (mediastinal tumor)
Decreased oncotic pressure (less common)
Hypoalbuminemia due to:
Malnutrition
Liver disease (decreased protein synthesis)
Nephrotic syndrome (increased protein loss)
Protein losing enteropathy

22. Edema due to microvascular injury
Leakage of fluid and proteins into the interstitial space and alveoli Pulmonary hydrostatic pressure is not elevated!
Due to:
Infections
Inhaled gases
Liquid aspiration
Drugs & chemicals
Shock, trauma
Radiation
Transfusion related

23. Question 2 Edema associated with left sided congestive heart failure:
is due to increased hydrostatic pressure in the alveolar capillaries.
causes hyaline membranes to form.
is more pronounced in the upper lobes
results in collapse of alveoli
is a result of microvascular injury

25. Adult Respiratory Distress Syndrome (ARDS)
Clinical syndrome of acute onset of severe respiratory distress with cyanosis & hypoxemia
Refractory to O2 therapy
X-ray  Diffuse infiltrate
Diffuse alveolar damage (DAD) is the histological manifestation of ARDS
Decreased lung compliance
No evidence of left-sided cardiac failure

26. ARDS Etiology >50% cases of ARDS: Sepsis
Diffuse pulmonary infections
Gastric aspiration
Mechanical trauma including head injury

27. ARDS Etiology Direct effects Systemic effects Aspiration Trauma
Gastric contents Sepsis
Hydrocarbons Acute pancreatitis
Salt or fresh water Multiple transfusions
Pulmonary infections Burns
Bacterial (gram positive and Cardiopulmonary bypass
gram negative) Reperfusion after lung transplant
Fungal Granulocytic leukemia
Mycobacterial Drug exposure
Viral Heroin
Mycoplasmal Methadone
Pneumocystic Acetylsalicyclic acid
Inhalation Placidyl
NO2, Cl2, SO2, NH2, O2 Paraquat
Smoke DIC
Fat embolism Uremia
Pulmonary contusion

28. Pathogenesis of ARDS
Imbalance of pro-inflammatory & anti-inflammatory mediators
Pulmonary macrophages increase IL-8, IL-1& TNF synthesis  endothelial activation, sequestration and activation of neutrophils
NEUTROPHILS ARE THOUGHT TO HAVE AN IMPORTANT ROLE IN THE PATHOGENESIS OF ARDS
Activated neutrophils  damage epithelium & endothelium vascular leakiness & loss of surfactant Fibrin secretion Hyaline membranes

29. Clinical course of ARDS
Early or acute or exudative phase:
First week (85% within 72 hrs), mortality is about 26-58%
Late or proliferative phase:
More than 1-2 weeks up to one year
Death due to progressive fibrosis in 40% of patients
Sequelae:
Decreased lung function due to interstitial fibrosis (restrictive lung disease, 80% of patients)
Cognitive, psychiatric abnormalities (30-50% of patients)
Physical weakness (50-60% of patients)

30. Acute (exudative) phase
Profound dyspnea & tachypnea
Increasing cyanosis and hypoxemia
Diffuse bilateral infiltrates on X-Ray

32. Normal
Acute Congestive phase

33. Diffuse Alveolar Damage
Edema

34. Congestion

35. Hyeline membranes: fibrin rich edema fluid + remnants of necrotic epithelial cells

36. Late or proliferative phase
Resorption of exudate and removal of dead cells by macrophages
Release of TGFβ and PDGF and replacement by:
Fibrosis
Epithelium
Proliferation of type II pneumocytes
Bronchoalveolar stem cells
Endothelium
Migration from adjacent capillaries
Marrow-derived endothelial progenitor cells

37. Interstitial fibrosis
Type II pneumocyte
proliferation
Residual hyaline
membranes

38. Organizing phase
Acute phase

39. Fibro-proliferation in ARDS

40. Advanced Interstitial Fibrosis “Honeycomb Lung”

41. Advanced Interstitial Fibrosis “Honeycomb Lung”

42. Neonatal Respiratory Distress Syndrome (NRDS)
Affects about 1% of newborn infants.
Is the leading cause of death in preterm infants.
Is histologically characterized by hyaline membranes covering the alveolar walls.

43. NRDS Presentation Preterm infant, appropriate for gestational age
Usually male, delivered by cesarean section & associated with maternal diabetes
Require resuscitation at birth  normal color established within 30 minutes difficulty breathing and cyanosis
Chest X-ray  ground-glass picture
Difficult to treat
If the baby survives for 3-4 days  excellent chance of recovery

44. NRDS Etiology
Incidence of NRDS is inversely proportional to gestational age (60% < 28 weeks; 30% between weeks; <5% in >34 weeks
Surfactant production  accelerated after 35th week gestation in fetus
High inspiratory pressures required at first breath
40% of residual air volume retained after first breath with normal surfactant
Surfactant deficiency collapse of lung after each breath infant works equally hard with each breath
Progressive collapse & reduced lung compliance

45. NRDS Risk factors Infants of diabetic mothers:
maternal hyperglycemia → compensatory fetal hyperinsulinemia → reduced surfactant synthesis
Infants born with cesarean section:
Labor increases surfactant synthesis
Conditions associated with intrauterine stress
Increased surfactant synthesis  lower risk of RDS

46. Fundamental defect is deficiency of pulmonary surfactant
NRDS Cause
Fundamental defect is deficiency of pulmonary surfactant

47. NRDS Pulmonary surfactant (I)
complex mixture of phospholipids synthesized & secreted by type 2 alveolar cells.
present at the air-liquid interface of alveolar lining layer

48. NRDS Pulmonary surfactant (II)
90% phospholipids & 10% proteins
1) Phospholipids
Phosphatidyl choline principle component
Phosphatidyl glycerol
2) Proteins
SP-A, hydrophilic
SP-B, hydrophobic
SP-C, hydrophobic
SP-D, hydrophilic

49. NRDS Pulmonary surfactant (III)
Phosphatidyl choline & Phosphatidyl glycerol are absolute requirements for surfactant function
SP-B and SP-C are hydrophobic and may be needed to carry phosholipid molecules to air liquid interface
Mutations of SP-B & SP-C genes  severe respiratory failure
SP-A and SP-D are hydrophilic; bind microbial surface antigens and act as opsonins

50. NRDS Pathophysiology

51. NRDS Prognosis Maturity and birth weight
Promptness of institution of therapy

52. NRDS Diagnosis and prevention
Analysis of amniotic fluid phospholipids  good estimate of surfactant level in fetal lung
Prevention:
Inducing maturation in fetus at risk
Prophylactic administration of surfactant to premature infants
Antenatal corticosteroids administration
After birth:
Surfactant replacement therapy
Oxygen

53. NRDS Complications (I)
Retrolental fibroplasia (retina is incompletely vascularized due to oxygen therapy)
decrease in VEGF
endothelial cell apoptosis
retinal tissue ischemic
retinal scarring
scar tissue can pull the retina off the back of eye
retinal detachment  visual impairment

54. NRDS Complications (II)
Bronchopulmonary dysplasia (BPD) due to oxygen therapy
Hyperoxemia, hyperventilation, prematurity, inflammatory cytokines & vascular mal-development
Defined clinically as oxygen dependence to 28 days post-natally
Oxygen delivery under high pressures  necrotizing bronchiolitis and alveolar septal injury
Recent years  milder injury arrest of lung maturation in the saccular stage of development (simplified acini)

55. Question 3
All of the following are true about hyaline membrane disease of the newborn is true EXCEPT:
It is most common in neonates less than 32 weeks gestational age
It can be prevented by administration of corticosteroids to the mother during gestation
It is characterized microscopically by dense eosinophilic proteinaceous material along the inner walls of the alveolar spaces
It is due to increased surfactant production by the lung
Oxygen therapy for hyaline membrane disease of the newborn may lead to bronchopulmonary dysplasia

57. Acute Interstitial Pneumonitis or Hamman–Rich syndrome
ARDS with interstitial lung disease in previously healthy patients
Older than 40 years of age, no sex predilection
Unknown cause, rapid progression to acute respiratory failure.
Mortality of 33% to 74%
Most deaths occur within 1-2 months
Substantial fraction of patients develop recurrent ALI

58. Diffuse alveolar hemorrhage Goodpasture syndrome
Proliferative, usually rapidly progressive glomerulonephritis with acute hemorrhagic interstitial pneumonitis
Antibodies against α3 chain of collagen IV
Diffuse alveolar hemorrhage with focal necrosis of alveolar walls, intra-alveolar hemorrhages, fibrous thickening of the septa, and type II pneumocyte hyperplasia.
Linear pattern of immunoglobulin deposition (usually IgG, sometimes IgA) in alveolar walls

59. Diffuse intra-alveolar hemorrhage with hemosiderin-laden macrophages
Iron stain
Robbins and Cotran Pathologic Basis of Disease, 9th ed.

60. Diffuse alveolar hemorrhage Idiopathic pulmonary hemosiderosis
Rare disease of immune-mediated but unknown etiology that has pulmonary manifestations and histologic features similar to Goodpasture syndrome but without renal manifestation or circulating antibodies

61. Diffuse alveolar hemorrhage Pulmonary angiitis (Wegener Granulomatosis)
Bilateral acute pneumonitis with nodules and cavitary lesions
Combination of small vessel necrotizing vasculitis (angiitis) and necrotizing granulomatous inflammation
PR3-ANCAs are present in close to 95% of cases
chronic sinusitis (90%), mucosal ulcerations of the nasopharynx (75%), and renal disease (80%)

62. Wegener granulomatosis
Vasculitis of a small artery with adjacent granulomatous inflammation including giant cells
large nodular cavitating lesions
Robbins and Cotran Pathologic Basis of Disease, 9th ed.